Recommendations for the prevention, screening, diagnosis, staging, and management of cervical cancer in areas with limited resources: Report from the International Gynecological Cancer Society consensus meeting.

Introduction: Nearly 85% of cervical cancer new cases are diagnosed in limited resources countries. Although several strategies have been proposed to reduce the disease burden, challenges remain to provide the best possible care. We report recommendations from an expert consensus meeting convened to address from prevention to management of cervical cancer in limited resources countries. Methods: The expert panel, composed by invited specialists from 38 developing countries in Africa, Asia, Eastern Europe, Latin America, and the Middle East, convened in Rio de Janeiro in September 2019, during the Global Meeting of the International Gynecological Cancer Society (IGCS). Panel members considered the published scientific evidence and their practical experience on the topics, as well as the perceived cost-effectiveness of, and access to, the available interventions. The focus of the recommendations was on geographic regions rather than entire countries because medical practice varies considerably in the countries represented. Resource limitation was qualified as limited access to qualified surgeons, contemporary imaging or radiation-oncology techniques, antineoplastic drugs, or overall funding for provision of state-of-the-art care. Consensus was defined as at least 75% of the voting members selecting a particular answer of the multiple-choice questionnaire, whereas the majority vote was considered as 50% to 74.9%. Results: Consensus was reached for 25 of the 121 (20.7%) questions, whereas for 54 (44.6%) questions there was one option garnering between 50% to 74.9% of votes (majority votes). For the remaining questions, considerable heterogeneity in responses was observed. Discussion: The implementation of international guidelines is challenging in countries with resource limitations or unique health-care landscapes. The development of guidelines by the health care providers in those regions is more reflective of the reality on the ground and may improve medical practice and patient care. However, challenges remain toward achieving that goal at political, economic, social, and medical levels.

Molecular Analysis of Short- versus Long-Term Survivors of High-Grade Serous Ovarian Carcinoma.

Despite having similar histologic features, patients with high-grade serous ovarian carcinoma (HGSC) often experience highly variable outcomes. The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, <3 years) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples was collected (12 LTS and 12 STS) and analyzed at DNA, RNA, and protein levels. OVCAR5 and OVCAR8 cell lines were used for in vitro validation studies. For in vivo studies, we injected OVCAR8 cells into the peritoneal cavity of female athymic nude mice. From RNAseq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change > 2; false discovery rate < 0.01). In the subsequent validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. CIBERSORT analysis showed that T cells (follicular helper) were found at higher levels in tumors from LTS than STS groups. In vitro data using OVCAR5 and OVCAR8 cells showed decreased proliferation with TMEM62 overexpression and positive correlation with a longevity-regulating pathway (KEGG HSA04213) at the RNA level. In vivo analysis using the OVCAR8-TMEM62-TetON model showed decreased tumor burden in mice with high- vs. low-expressing TMEM62 tumors. Our results demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes

The new world of poly-(ADP)-ribose polymerase inhibitors (PARPi) used in the treatment of gynecological cancers.

The clinical development of poly-(ADP)-ribose polymerase inhibitors (PARPi) began with the treatment of ovarian cancer patients harboring BRCA1/2 mutations and continues to be expanded to other gynecological cancers. Furthermore, The Cancer Genome Atlas (TCGA) analysis of endometrial and cervical cancers offered rationale that PARPi may be an option for treatment based on the molecular profiles of these cancer types. This review summarizes the current indications of PARPi, such as its role in the treatment and maintenance of recurrent ovarian cancer and for first-line maintenance therapy in advanced ovarian cancer. We also outline new concepts for PARPi therapy in other gynecological cancers such as endometrial and cervical cancers based on recent clinical data. Finally, we present potential future directions to continue exploring the world of PARPi resistance and combining PARPi with other therapies.

Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic.

Objectives: Approximately 60% of lung adenocarcinomas (LAs) carry mutations that can guide treatment with tyrosine-kinase inhibitors (TKI) and other targeted therapies. Data on activating mutations in EGFR and other tyrosine-kinase receptor (TKR) genes in highly admixed populations, such as that of Brazil, are scarce. In this study, we comprehensively analyzed the actionable alteration profile of LA in Brazilian patients. Materials and Methods: EGFR driver mutation data were collected from a large Brazilian LA cohort covering an 8-year period of molecular testing in a single institution. Tests were performed using three distinct methods, and demographic and histopathological data were analyzed. For a subset of patients, driver mutations in KRAS, NRAS, and BRAF and gene fusions involving TKR genes (before TKI treatment) and EGFR T790M (after TKI treatment) were assessed. Results: EGFR mutations were detected in 25% of 1,316 LAs evaluated, with exon 19 deletions and exon 21 L858R TKI sensitizing mutations representing 72.5% of all mutations. Mutation rates were higher in women and non-smokers (p < 0.001). Next-generation sequencing was very sensitive, with a lower rate of inconclusive results compared with Sanger sequencing and pyrosequencing. EGFR/RAS/BRAF hotspot gene panels were applied in 495 LA cases and detected oncogenic mutations in 51.3% of samples, most frequently in EGFR (22.4%) and KRAS (26.9%). In subgroups of 36 and 35 patients, gene fusions were detected in 11.1% of tumors and EGFR T790M resistance mutations were detected in 59% of plasma samples from patients previously treated with TKI, respectively. Conclusion: This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations in EGFR and other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.

Can HIPEC be used against platinum-resistance and for inducing sensitivity to PARP inhibitors in ovarian cancer?

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a main comprehensive treatment of epithelial ovarian cancer (EOC). Despite much criticism to this approach, HIPEC has shown cost-effective benefits in both progression-free survival and overall survival for high tumor burden with no important impairment on patient-reported quality of life. On the other hand, the landscape of EOC treatment is changing rapidly and poly (ADP-ribose) polymerase inhibitors (PARPi) currently play an important role in the management of EOC based on recent trials. At this point, an important question to be scrutinized is what to expect from up-front HIPEC in the era of amazing benefits by the PARPi. Herein, we discuss the promising role of combining PARPi and HIPEC in the management of advanced EOC.

Discrepancy in calculated and measured glomerular filtration rates in patients treated with PARP inhibitors.

OBJECTIVE: To describe discrepancies in calculated and measured glomerular filtration rate in patients using PARP (poly ADP ribose polymerase) inhibitors who had an elevation in serum creatinine levels. METHODS: Retrospective cohort, single center study. Patients included were those with ovarian or endometrial cancer taking olaparib, rucaparib or niraparib, and in in whom an increased serum creatinine was identified. The study cohort included those who also underwent technetium-99m radioisotope renography (glomerular filtration rate (GFR) scan). The main objective is to describe the discrepancies in calculated glomerular filtration rate using the Cockcroft-Gault method and measured glomerular filtration rate using a GFR scan. RESULTS: 211 patients were included in the study; 64 (30%) had on-treatment elevated serum creatinine, and 23 (36%) underwent a GFR scan. 32 GFR scans were performed (six patients had more than one scan). Using a clinical cut-off ≥50 mL/min as normal renal function, both calculated and estimated glomerular filtration rates were below normal in 6 of 32 GFR scans. In those patients undergoing a GFR scan, serum creatinine had risen a median 49% (IQR 20-66%, range 0-144%) above baseline. Discordance between a calculated low glomerular filtration rate and an estimated normal glomerular filtration rate occurred in 63% (range of glomerular filtration rate discrepancy: -46% to +237%). Despite increases in serum creatinine on therapy and a subsequent significant decline in the per patient calculated creatinine clearance (mean 65.6 mL/min vs 43.4 mL/min; p<0.0001), the estimated glomerular filtration rate from the renal scan was nearly identical to the patient's baseline (65.6 mL/min vs 66.1 mL/min; p=0.89). CONCLUSIONS: Serum creatinine elevation in patients taking PARP inhibitors may not be associated with a true decrease in glomerular filtration rate. A high index of suspicion should be maintained for alternative causes of elevated serum creatinine in patients treated with PARP inhibitors who lack other sources of renal injury.

Risk of fatigue and anemia in patients with advanced cancer treated with olaparib: A meta-analysis of randomized controlled trials.

INTRODUCTION: PARP inhibitors are a new class of drugs that are currently being studied in several malignancies. Olaparib is FDA-approved for advanced breast cancer and advanced ovarian cancer patients. Fatigue and anemia are among the most common cancer and treatment-related symptoms. Therefore, we conducted a meta-analysis of randomized controlled trials (RCT) to characterize the incidence and relative risks (RRs) of fatigue and anemia associated with olaparib. METHODS: PubMed, Cohrane, Embase and abstracts presented at the annual meeting of the American Society of Clinical Oncology (ASCO) were searched for articles published from 2000 to June 2018. The eligible studies were phase II and III RCT of olaparib. Safety profile from each selected study was evaluated for all-grade and high-grade fatigue and anemia adverse events. Summary incidences and the RR, with 95% confidence intervals, of all-grade and high-grade events were calculated using random-effects or fixed-effects model based on the heterogeneity of selected studies. RESULTS: A total of 9 trials were selected, and included 2074 patients with advanced ovarian, gastric, prostate, lung or breast cancer. 908 patients received placebo/control treatments and 1166 received olaparib alone or combination with other active cancer treatments. The RR of all-grade and high fatigue was 1.24 (95% CI, 1.10-1.39) and 1.71 (95% CI, 1.06-2.77), respectively. The RR of all-grade and high-grade anemia was 2.10 (95% CI, 1.48-2.98) and 3.15 (95% CI, 1.73-5.71), respectively. CONCLUSION: Our findings suggest that the olaparib treatment is associated with an increased risk of fatigue and anemia. Since fatigue and anemia are very common treatment related adverse events, and both can impair the quality of life of patients, it is important to identify them early and manage it accordingly in order to optimize the overall treatment.

Poly-ADP-ribose polymerase inhibitor use in ovarian cancer: expanding indications and novel combination strategies.

The use of poly(ADP-ribose) polymerase (PARP) inhibition is transforming care for the treatment of ovarian cancer, with three different PARP inhibitors (PARPi) gaining US Food and Drug Administration approval since 2014. Given the rapidly expanding use of PARPi, this review aims to summarize the key evidence for their use and therapeutic indications. Furthermore, we provide an overview of the development of PARPi resistance and the emerging role of PARPi combination therapies, including those with anti-angiogenic and immunotherapeutic agents.

Exploring and comparing adverse events between PARP inhibitors.

Ovarian cancer remains one of the most challenging malignancies to treat. Targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as one of the most exciting new treatments for ovarian cancer, particularly in women with BRCA1 or BRCA2 mutations or those without a functional homologous recombination repair pathway. Perhaps the most advantageous characteristic of PARP inhibitors is their mechanism of action, which targets cancer cells on the basis of their inherent deficiencies while seemingly avoiding normally functioning cells. Although health-care providers might assume a low toxicity profile because of their specific mechanism of action, PARP inhibitors are not completely benign and overall show a class effect adverse-event profile. Further complicating this situation, three different PARP inhibitors have been approved by the US Food and Drug Administration since 2014, each with their own specific indications and individual toxicity profiles. The diversity of adverse events seen both within and across this class of drug underscores the importance of having a comprehensive reference to help guide clinical decision making when treating patients. This Review characterises and compares all toxicities associated with each PARP inhibitor, both in monotherapy and in novel combinations with other drugs, with a particular focus on potential management strategies to help mitigate toxic effects. Although the excitement surrounding PARP inhibitors might certainly be warranted, a thorough understanding of all associated toxicities is imperative to ensure that patients can achieve maximal clinical benefit.

Rucaparib in ovarian cancer: extending the use of PARP inhibitors in the recurrent disease.

Rucaparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP) PARP1, PARP2 and PARP3, and to a lesser extent, PARP4, PARP10, PARP12, PARP15 and PARP16. Study 10 and ARIEL2 evaluated the use of rucaparib as treatment in patients with recurrent high-grade ovarian carcinoma and resulting in approval of rucaparib for patients with both germline and somatic BRCA mutation. Data from the Phase III trial ARIEL3 led to approval in platinum-sensitive disease as maintenance. This article reviews the efficacy, safety, pharmacokinetics and pharmacodynamics of rucaparib as well as future and ongoing trials.

Response to pembrolizumab in a heavily treated patient with metastatic ovarian carcinosarcoma.

BACKGROUND: Ovarian carcinosarcoma is a rare malignancy associated with a high rate of cancer-related mortality even at early stages. Guidelines for systemic treatment have been difficult to establish because the disease is commonly excluded from prospective clinical trials. Ovarian carcinosarcoma is usually managed as high-grade epithelial ovarian cancer despite major histologic differences. Owing to the rarity and poor prognosis of ovarian carcinosarcoma, salvage treatments and their efficacy have been poorly described. CASE PRESENTATION: A patient heavily treated for ovarian carcinosarcoma showed an objective response to an immune checkpoint inhibitor, pembrolizumab. Pembrolizumab in this patient appeared to provide tumor control in multifocal metastatic sites. CONCLUSIONS: Pembrolizumab should be evaluated in prospective trials for the treatment of ovarian carcinosarcoma and further work is needed to identify patients most likely to respond to this type of intervention.

Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy.

Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor and potent inhibitor of PARP1, PARP2 and PARP3 enzymes. Phase II and III trials have documented that rucaparib has single-agent antitumor activity in patients with high-grade ovarian carcinoma, with both BRCA-mutated (germline and somatic) and with homologous recombination deficiency (HRD). Rucaparib as a maintenance treatment showed increased progression-free survival in patients with ovarian carcinoma who achieved a response to platinum-based chemotherapy, with an acceptable safety profile. The approval of this drug, along with the companion diagnostic FoundationFocus CDxBRCA test represents an important new therapeutic option in the treatment of ovarian cancer. This article reviews the mechanisms of action, safety, pharmacokinetics and pharmacodynamics and indications for use of rucaparib as well as future trials.